UPREGULATION OF CHOLECYSTOKININ RECEPTOR EXPRESSION IN SENSORY NEURONS BY NERVE GROWTH FACTOR

Brian Lew, Miaw-Chyi Luo, Frank Porreca and Josephine Lai

Previous evidence shows that the neuropeptide cholecystokinin (CCK) acts to diminish the efficacy of opioids such as morphine to suppress pain, while antagonists to the CCK receptors enhance the analgesic actions of morphine. Thus, it has been proposed that endogenous CCK may have anti-opioid actions when it is released from spinal cord neurons in the dorsal horn. Changes in the expression of CCK in the spinal cord and of CCK receptors in sensory neurons have also been observed in animal models of nerve injury, leading to the hypothesis that the anti-opioid actions of CCK may contribute to the limited efficacy of morphine in suppressing pain that arises from the nerve injury (neuropathic pain). This study evaluates the expression of CCK receptors (both A and B subtypes) in the primary afferent sensory neurons upon repeated peripheral administration of nerve growth factor (NGF), which rapidly induces a local, abnormal sensitivity to heat stimuli. Male Sprague-Dawley rats were injected subcutaneously in one hind paw with saline or 100 ng of NGF once daily for 3 days. On day four, the animals were sacrificed and the ipsilateral and contralateral L4/L5 DRGs were isolated. Total RNA was extracted from these samples and analyzed by RT-PCR using primers specific for CCK_A or CCK_B receptor transcripts; glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was co-amplified in these samples as an internal reference for semi-quantitative analysis. Both types of CCK receptors are found to be upregulated after NGF treatment when compared with saline controls. This upregulation of CCK receptors in the sensory neurons may enhance their sensitivity to spinal CCK. To further determine the relevance of this observation to neuropathic pain and morphine efficacy, we are currently extending our analysis in a spinal nerve ligation injury model of neuropathic pain.

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